Field of the Invention
[0001] The present invention relates to a 5-thia- ω -substituted phenyl-prostaglandin E
alcohol.
[0002] More detail, it relates to a 5-thia- ω-substituted phenyl-prostaglandin E alcohol
of the formula (I)

(wherein, all the symbols are the same meaning as defined hereinafter),
a process for producing it and a pharmaceutical composition it as an active ingredient.
Background
[0003] Prostaglandin E
2 (abbreviated as PGE
2) has been known as a metabolite in the arachidonate cascade. It has been known that
PGE
2 possesses cytoprotective activity, uterine contractile activity, a pain-inducing
effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive
effect on gastric acid secretion, hypotensive activity and diuretic activity etc.
[0004] A recent study has proved existence of various PGE
2 subtype receptors possessing a different physical role from each other. At present,
four receptor subtypes are known and they are called EP
1, EP
2, EP
3, EP
4 (Negishi M. et al, J. Lipid Mediators Cell Signaling,
12, 379-391 (1995)).
[0005] It is thought that EP
4 subtype receptor relates to inhibition of producing TNF-α and acceleration of producing
IL-10. Therefore, the compounds which can bind on EP
4 subtype receptor strongly are expected to be useful for the prevention and/or treatment
of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis
(ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic
lupus erythematosus etc., and rejection after organ transplantation etc.), asthma,
abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis,
nephritis, renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory
response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's
disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's
disease, hypercytokinemia at dialysis, multiple organ failure, and shock etc. Further,
it is thought that EP
4 subtype receptor relates to sleeping disorder and blood platelet aggregation, so
such compounds are expected to be useful for the prevention and/or treatment of these
diseases.
[0006] The present inventors et al. have found out that 5-thia-prostaglandin derivatives
of the following formula (A) are useful as a compound which satisfies these purposes
and have filed a patent application relates to such compounds (WO00/03980). These
compounds can bind on EP
4 subtype receptor selectively and binds on the other subtype receptors weakly, so
they show no any other activities. Therefore they are expected to be drugs possessing
less side effects. 5-Thia-ω-substituted phenyl-prostaglandin E derivatives of the
following formula (A):

(wherein,
R1A is hydroxy, C1-6 alkyloxy, or the formula: NR6AR7A (in which, R6A and R7A are, independently, hydrogen or C1-4 alkyl),
R2 is oxo, halogen or the formula: O-COR8A (in which, R8A is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl)),
R3A is hydrogen or hydroxy,
R4Aa and R4Ab are, independently, hydrogen or C1-4 alkyl,
R5A is phenyl substituted with the following group:
i) 1-3 of substituent(s) selected from the group consisting of
C1-4 alkyloxy-C1-4 alkyl,
C2-4 alkenyloxy-C1-4 alkyl,
C2-4 alkynyloxy-C1-4 alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,
phenyloxy-C1-4 alkyl,
phenyl-C1-4 alkyloxy-C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl,
C2-4 alkenylthio-C1-4 alkyl,
C2-4 alkynylthio-C1-4 alkyl,
C3-7 cycloalkylthio-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl,
phenylthio-C1-4 alkyl, or
phenyl-C1-4 alkylthio-C1-4 alkyl,
ii)
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4 alkyloxy-C1-4 alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or
C1-4 alkylthio-C1-4 alkyl and halogen,
iii) haloalkyl or hydroxy-C1-4 alkyl, or
iv) C1-4 alkyl and hydroxy;
--- is a single bond or a double bond,
with the proviso that when R
2A is the formula: O-COR
8A, bond of C8-C9 is a double bond) and cyclodextrin clathrate thereof are described
in the specification of WO00/03980.
Disclosure of the Invention
[0007] The present inventors et al. have studied to find out the stable compounds which
can bind on EP
4 subtype receptor specifically, and do not bind on any other EP subtype receptors
nor any other prostanoid receptors. The present inventors have found out 5-thiaprostaglandin
wherein a substituted phenyl is introduced into ω-chain have achieved this object,
and then filed the said patent application (WO00/03980).
[0008] The present inventors et al. have confirmed that converting carboxy group of the
compounds described in the said patent application into hydroxy group (alcohol) improved
an absorption of the compounds into the living body and then, have completed the present
invention. The compounds of the formula (I) of the present invention may be converted
into carboxylic acid which is an active compound by oxidation in the living body.
The said active carboxylic acid possesses an activity to bind on EP
4 subtype receptor strongly and bind on the other prostanoid receptors including the
other subtype receptors weakly, and a sufficient stability as a drug.
[0009] That is to say, the present invention relates to
(1) a 5-thia- ω-substituted phenyl-prostaglandin E alcohol of the formula (I)

(wherein, --A-- is absent or --A-- is methylene or ethylene,
R1 is hydrogen, C1-6 alkyl, phyenyl-C1-6 alkyl, C2-6 alkanoyl, or phyenyl-C2-6 alkanoyl,
R2 is oxo or halogen,
R3 is hydrogen or hydroxy,
R4a and R4b are, independently, hydrogen or C1-4 alkyl,
R5 is phenyl substituted with the following group:
i) 1-3 of group selected from the group consisting of
C1-4 alkyloxy-C1-4 alkyl,
C2-4 alkenyloxy-C1-4 alkyl,
C2-4 alkynyloxy-C1-4 alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,
phenyloxy-C1-4 alkyl,
phyenyl-C1-4 alkyloxy-C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl,
C2-4 alkenylthio-C1-4 alkyl,
C2-4 alkynylthio-C1-4 alkyl,
C3-7 cycloalkylthio-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl,
phenylthio-C1-4 alkyl, and
phyenyl-C1-4 alkylthio-C1-4 alkyl,
ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4 alkyloxy-C1-4 alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or
C1-4 alkylthio-C1-4 alkyl and halogen,
iii) haloalkyl or hydroxy-C1-4 alkyl, or
iv) C1-4 alkyl and hydroxy;
--- is a single bond or a double bond)
or cyclodextrin clathrate thereof,
(2) a process for producing it and
(3) a pharmaceutical composition comprising it as an active ingredient.
[0010] In the formula (I), C1-4 alkyl in R
4a, R
4b and R
5 means methyl, ethyl, propyl, butyl and isomers thereof.
[0011] In the formula (I), C1-6 alkyl in R
1 means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
[0012] In the formula (I), C2-6 alkyl in R
1 means ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
[0013] In the formula (I), C2-6 alkanoyl in R
1 means acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and isomers thereof.
[0014] In the formula (I), C2-4 alkenyl in R
5 means vinyl, propenyl, butenyl and isomers thereof.
[0015] In the formula (I), C2-4 alkynyl in R
5 means ethynyl, propynyl, butynyl and isomers thereof.
[0016] In the formula (I), C3-7 cycloalkyl in R
5 means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
[0017] In the formula (I), halogen in R
2 and R
5 means fluorine, chlorine, bromine and iodine.
[0018] In the present invention, the symbol

means single bond or double bond. Further, unless otherwise specified, in the present
invention, the symbol

means that the substituent attached thereto is in front of the sheet, the symbol

means that the substituent attached thereto is behind the sheet and the symbol

means that there is a mixture of substituents in front of and behind the sheet or
that the substituent attached thereto may be in front of or behind the sheet as would
be clear to the person skilled in the art.
[0019] Unless otherwise specified, all isomers are included in the present invention. For
example, alkyl, alkenyl, alkynyl, alkylene group means straight-chain or branched-chain
ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer),
isomers generated from asymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,
diastereomer), optically active isomers (D-, L-, d-, I-isomer), polar compounds generated
by chromatographic separation (more polar compound, less polar compound), equilibrium
compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included
in the present invention.
[0020] In the formula (I), the substituent(s) of phenyl in R
5 is preferably substituted at 3-position, 3-position and 4-position, and 3-position
and 5-position.
[0021] In the formula (I), each group (i) to (iv) as the substituent(s) of phenyl in R
5 means as follows:
group i) means 1, 2 or 3 of alkyloxyalkyl etc.,
group ii) means at least one alkyloxyalkyl etc. and at least one alkyl, alkyloxy,
hydroxy or halogen,
group iii) means alkyl substituted with 1 or 2 of halogen or hydroxy and
group iv) means at least one alkyl and at least one hydroxy.
[Cyclodextrin clathrate]
[0023] The compounds of the present invention of the formula (I) may be converted into the
corresponding cyclodextrin clathrates by the method described in the specification
of Japanese Patent Application Kokoku Sho 50-3362, 52-31404 or 61-52146 using α-,
β- or γ-cyclodextrin or a mixture thereof. Converting into the corresponding cyclodextrin
clathrates serves to increase the stability and solubility in water of the compounds,
and therefore it is useful in the use for pharmaceuticals.
[Process for producing the compounds of the present invention]
[0024] The compounds of the formula (I)

(wherein, all the symbols are the same meaning as defined hereinbefore) may be prepared
from the compounds of the formula (II)

(wherein,
R1-1 is C1-6 alkyl, phenyl-C1-6 alkyl, C2-6 alkanoyl, phenyl-C2-6 alkanoyl, or a protecting
group of hydroxy which is removed under an acidic condition,
R3-1 is hydrogen or hydroxy group protected by a protecting group of hydroxy which is
removed under an acidic condition,
R10 is a protecting group of hydroxy which is removed under an acidic condition,
R5-1 is the same meaning of R5 provided that hydroxy group in the group represented by R5-1 is protected by a protecting group which is removed under an acidic condition, and
the other symbols are the same meaning as defined hereinbefore)
by reaction for removal of a protecting group under an acidic condition.
[0025] A protecting group of hydroxy which is removed under an acidic condition includes,
for example, t-butyldimethylsilyl, triphenylmethyl, and tetrahydropyran-2-yl (THP)
etc.
[0026] Hydrolysis under an acidic condition has been known. This reaction may be carried
out, for example, in an organic solvent which is admissible with water (e.g., tetrahydrofran,
methanol, ethanol, dimethoxyethane, acetonitrile or mixture thereof etc.), using an
inorganic acid (e.g., hydrochloric acid, phosphoric acid, hydrofluoric acid, hydrogen
fluoride-pyridine etc.) or an organic acid (e.g., acetic acid, tosylic acid, trichloroacetic
acid etc.) at temperature of 0-50°C.
[0027] The compounds of the formula (II) may be prepared by the following Reaction Schemes
1-3.
[0028] Each symbol in Reaction Schemes means as follows or same meaning defined hereinbefore:
Ms: methanesulfony,
Ts: p-toluenesulfonyl,
R2-1: halogen,
Ac: acetyl,
TMS: trimethylsilyl.

[Starting materials and reagents]
[0029] Each Reaction in the said Reaction Schemes may be carried out by known methods. In
the said Reaction Schemes, the compounds of the formulae (III), (V) and (XII) as starting
materials have been known or may be prepared easily by known methods.
[0030] For example, the compounds of the formula (III) wherein R
3-1 is THP have been described in J. Am. Chem. Soc.,
98, 1490 (1971).
[0031] The other starting materials and reagents in the present invention are known per
se or may be prepared by known methods.
[0032] In each reaction in the present specification, reaction pr oducts may be purified
by conventional techniques. For example, purification may be carried out by distillation
at atmospheric or reduced pressure, by high performance liquid chromatography, by
thin layer chromatography or by column chromatography using silica gel or magnesium
silicate, by washing or by recrystallization. Purification may be carried out after
each reaction, or after a series of reactions.
[Pharmacological Activities]
[0033] The compounds of the present invention of the formula (I) may be converted into carboxylic
acids by oxidation in the living body. As described in the specification of WOOO/03980,
the corresponding carboxylic acids can bind strongly on EP
4 subtype receptor which is one of PGE
2 receptors and show an activity on it.
[0034] For example, in the laboratory experiments, the inhibitory action on producing TNF-
α induced by lipopolysaccharide (LPS) or the conversion of the compounds of the present
invention into carboxylic acids in the living body has been confirmed by assaying
the concentration in the blood plasma of rat.
[inhibitory action on producing TNF- α]
[0035] LPS (10µg/2 ml/kg) was administered into a tail vein of SD-strain male rat. Blood
was collected from an abdominal large vein with heparin after 90 minutes from administration
to prepare blood plasma. The amount of TNF- α in the blood plasma was determined by
using ELISA Kit (Rat TNF- α Immunoassay kit, Biosource Co.). Each compound of the
present invention was administered orally before 30 minutes from administration of
LPS. The effective dose (IC50) was defined as the dose at which the test compound
showed 50% inhibition on producing TNF- α in blood plasma, when the amount of producing
TNF- α in the control group (administration of LPS, non-administration of test compound)
was as 100%. The results are shown in Table 4.
Table 4
Example No Example No |
Effective dose IC50 (µg/kg) p.o. |
1 |
117 |
1(1) |
57.4 |
[Converting into carboxylic acid in the living body]
[0036] The compound of Example 1(1) (1 mg/kg; alcohol compound) was administered into SD-strain
male rat by intravenous route to determine each concentration of the said compound
and corresponding carboxylic acid, i.e., (11 α ,15 α ,13E)-9-oxo-11,15-dihydroxy-1
6-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid (corresponding
carboxylic acid) in blood plasma. The test solution may be prepared from a physiological
saline solution containing 0.3%ethanol and 0.1 % POLYSORBATE 80. The concentration
was determined by using liquid chromatograph mass spectrometer (LC/MS/MS). The results
are shown in Table 5.
Table 5
Compounds |
Concentration in blood plasma AUC0-∞ (ng · hr/ml) |
Example 1(1) |
462±78 |
corresponding carboxylic acid |
99±26 |
[Discussion]
[0037] It has been confirmed that the alcohol compounds which were administered into living
body were converted into carboxylic adds in it by oxidation.
[Toxicity]
[0038] The toxicity of the compounds of the formula (I) of the present invention is very
low and therefore, it is confirmed that these compounds are safe for use as medicine.
Industrial Application
[Application for pharmaceuticals]
[0039] The compounds of the present invention of the formula (I) may be converted into carboxylic
acids by oxidation in the living body. Such carboxylic acids can bind on PGE
2 receptor and show the activity on it. Particularly, they bind on EP
4 subtype receptor strongly, so the compounds of the formula (I) are expected to be
useful for the prevention and/or treatment of immunological diseases (autoimmune diseases
such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome,
chronic rheumarthrosis and systemic lupus erythematosus etc., and rejection after
organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death,
lung failure, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension,
myocardiac ischemia, systemic inflammatory response syndrome, sepsis, hemophagous
syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn,
systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at
dialysis, multiple organ failure, and shock etc. Further, it is thought that EP
4 subtype receptor relates to sleeping disorder and blood platelet aggregation, so
the compounds of the present invention are also expected to be useful for the prevention
and/or treatment of such diseases.
[0040] The carboxylic acids converted from the compounds of the present invention of the
formula (I) by oxidation might bind weakly on the subtypes receptors other than EP
4 subtype receptor do not express other effects, therefore such compounds are expected
to be an agent having less side effect.
[0041] For the purpose above described, the compounds of the formula (I) of the present
invention or cyclodextrin clathrate thereof may be normally administered systematically
or locally, usually by oral or parenteral administration.
[0042] The doses to be administered are determined depending upon age, body weight, symptom,
the desired therapeutic effect, the route of administration, and the duration of the
treatment etc. In the human adult, the doses per person per dose are generally between
1 µg and 100 mg, by oral administration, up to several times per day, and between
0.1 µg and 10 mg, by parenteral administration (preferred into vein) up to several
times per day, or continuous administration between 1 and 24 hrs. per day into vein.
[0043] As mentioned above, the doses to be used depend upon various conditions. Therefore,
there are cases in which doses lower than or greater than the ranges specified above
may be used.
[0044] The compounds of the present invention may be administered as solid compositions,
liquid compositions or other compositions for oral administration, or as injections,
liniments or suppositories etc. for parenteral administration.
[0045] Solid compositions for oral administration include compressed tablets, pills, capsules,
dispersible powders, and granules etc.
[0046] Capsules contain hard capsules and soft capsules.
[0047] In such compositions, one or more of the active compound(s) is or are, admixed with
at least one inert diluent such as lactose, mannitol, mannit, glucose, hydroxypropyl
cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate
aluminate.
[0048] The compositions may also comprise, as is normal practice, additional substances
other than inert diluents: e.g. lubricating agents such as magnesium stearate, disintegrating
agents such as cellulose calcium glycolate, and assisting agents for dissolving such
as glutamic acid, asparaginic acid. The tablets or pills may, if desired, be coated
with film of gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose
or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And
further, coating may include containment within capsules of absorbable materials such
as gelatin.
[0049] Liquid compositions for oral administration include pharmaceutically-acceptable emulsions,
solutions, syrups and elixirs etc. In such liquid compositions, one or more of the
active compound(s) is or are comprised in inert diluent(s) commonly used in the art
(for example, purified water, ethanol etc.). Besides inert diluents, such compositions
may also comprise adjuvants such as wetting agents, suspending agents, sweetening
agents, flavouring agents, perfuming agents and preserving agents.
[0050] Other compositions for oral administration include spray compositions which may be
prepared by known methods and which comprise one or more of the active compound(s).
Spray compositions may comprise additional substances other than inert diluents: e.g.
stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity,
isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation
of such spray compositions, for example, the method described in the United States
Patent No. 2868691 or 3095355 may be used.
[0051] Injections for parenteral administration include sterile aqueous or nonaqueous solutions,
suspensions and emulsions. Aqueous solutions or suspensions include distilled water
for injection and physiological salt solution. Non-aqueous solutions or suspensions
include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol
such as ethanol, POLYSORBATE80 (registered trade mark) etc.
[0052] Such compositions may comprise additional diluents: e.g. preserving agents, wetting
agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents
such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid).
They may be sterilized for example, by filtration through a bacteria-retaining filter,
by incorporation of sterilizing agents in the compositions or by irradiation. They
may also be manufactured in the form of sterile solid compositions which can be dissolved
in sterile water or some other sterile diluent for injection immediately before use.
[0053] Other compositions for parenteral administration include liquids for external use,
and endermic liniments, ointments, suppositories and pessaries which comprise one
or more of the active compound(s) and may be prepared by known methods.
Best Mode to carry out the Invention
[0054] The following Reference Examples and Examples are intended to illustrate, but not
limit, the present invention.
[0055] The solvents in parentheses in chromatographic separations and TLC show the developing
or eluting solvents and the ratios of the solvents used are by volume.
[0056] The solvents in parentheses in NMR show ones used for measurement.
Reference Example 1
(9 α,15α,13E)-1-t-butyldimethylsilyloxy-9-hydroxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en
[0057]

[0058] (9α,11α,15α,13E)-6-Acetylthio-9-trimethylsilyloxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-1,2,3,4,5,17,18,19,20-nonanorprost-13-en
(280 mg; prepared by the same procedure described in Reference Example 27 in the specification
of WO00/03980) and 1-t-butyldimethylsilyloxy-4-iodobutane (345 mg) were dissolved
into methanol. Thereto, potassium carbonate (152 mg) was added. The mixture was stirred
for 2 hours at room temperature. After termination of reaction, ether was added to
reaction solution. The mixture was washed by water and a saturated saline solution,
dried over by anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified with silica gel chromatography (hexane : ethyl acetate =
4 : 1) to obtain the title compound (139 mg) having the following physical data.
TLC: Rf 0.52 (hexane : ethyl acetate = 2 : 1);
NMR(CDCl
3): δ 7.3-7.1 (m, 4H), 5.55-5.2 (m, 2H), 4.75-4.45 (m, 1H), 4.42 (s, 2H), 4.3-4.2 (m,
2H), 3.62 (t, J = 5Hz, 2H), 3.38 (s, 3H), 3.4-3.2 (m, 2H), 3.0-2.7 (m, 2H), 2.6-2.4
(m, 4H), 2.4-2.2 (m, 1H), 2.05-1.85 (m, 2H), 1.85-1.3 (m, 15H), 0.89 (s, 9H), 0.05
(s, 6H).
Reference Example 2
(15 α,13E)-1-t-butyldimethylsilyloxy-9-oxo-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en
[0059]

[0060] To a solution of (9 α,15α,13E)-1-t-butyldimethylsilyloxy-9-hydroxy-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en
(139 mg; prepared in Reference Example 1) in ethyl acetate (1.0 ml), isopropyldiethylamine
(0.24 ml) was added. The mixture was cooled with ice. A solution of sulfur trioxide-pyridine
complex (110 mg) in dimethylsulphoxide (DMSO; 1 ml) was added at a dropwise thereto
for 1 minute. After stirring the mixture for 20 minutes, water was added thereto.
The mixture was extracted with ethyl acetate. The organic layer was washed by 1N hydrochloric
acid, water, a saturated solution of sodium hydrogen carbonate, a saturated saline
solution, succeedingly, dried over by magnesium sulfate, and concentrated under reduced
pressure to obtain the title compound having the following physical data.
TLC: Rf 0.63 (hexane : ethyl acetate = 2:1).
Example 1
(15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
[0061]

[0062] To a mixture solvent of acetonitlile (2 ml) and methanol (1 ml), (15α,13E)-1-t-butyldimethylsilyloxy-9-oxo-15-(2-tetrahydropyranyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en
(prepared in Reference Example 2) was dissolved. Thereto, 0.1N hydrochloric acid (1
ml) was added. The mixture was stirred for 2 hours at 35 °C. After termination of
reaction, a saturated solution of sodium hydrogen carbonate was added thereto. The
mixture was extracted with ethyl acetate two times, washed by a saturated saline solution,
dried over by magnesium sulfate and concentrated under reduced pressure. The residue
was purified with silica gel chromatography (hexane : ethyl acetate = 1 : 2 to 1 :
3) to obtain the title compound (72 mg) having the following physical data.
TLC: Rf 0.25 (ethyl acetate : hexane = 2:1);
NMR(CDCl
3): δ 7.3-7.1 (m, 4H), 5.75-5.6 (m, 2H), 4.44 (s, 2H), 4.4-4.3 (m, 1H), 3.65 (t, J
= 6Hz, 2H), 3.41 (s, 3H), 2.9-2.7 (m, 2H), 2.7-2.3 (m, 6H), 2.3-2.0 (m, 3H), 2.0-1.5
(m, 9H).
Examples 1(1)-1(4)
[0063] By the same procedure as described in Reference Examples
1 and
2 and Example 1, the compounds having the following physical data were obtained.
Example 1(1)
(11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
[0064]

TLC: Rf 0.18 (ethyl acetate);
NMR(CDCl
3): δ 7.35-7.17 (m, 4H), 5.77 (dd, J = 15.0, 6.0Hz, 1H), 5.54 (dd, J = 15.0, 8.0Hz,
1H), 4.48-4.38 (m, 3H), 4.00-3.90 (m, 1H), 3.68-3.63 (m, 2H), 3.42 (s, 3H), 3.01-2.21
(m, 11H), 1.92-1.55 (m, 8H).
Example 1(2)
(11 α,15α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methyl-4-hydroxyphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
[0065]

TLC: Rf 0.19 (ethyl acetate : methanol = 50:1);
NMR(CDCl
3): δ 7.0-6.7 (m, 3H), 5.68 and 5.53 (dd, J = 15, 8Hz, 1H), 5.57 and 5.35 (dd, J =
15, 9Hz, 1H), 4.2-3.9 (m, 2H), 3.65-3.6 (br, 2H), 2.8-2.0 (m, 16H), 2.0-1.5 (m, 6H),
1.32 and 1.20 (d, J = 7Hz, 3H).
Example 1(3)
(11 α,15α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
[0066]

TLC: Rf 0.08 (ethyl acetate);
NMR(CDCl
3): δ 7.36-7.10 (m, 4H), 5.71 (dd, J = 15.3, 6.6Hz, 0.5H), 5.62 (dd, J = 15.6, 5.7Hz,
0.5H), 5.53 (dd, J = 16.0, 8.1Hz, 0.5H), 5.47 (dd, J = 15.3, 7.8Hz, 0.5H), 4.49-4.38
(m, 2H), 4.25-4.15 (m, 1H), 3.99-3.76 (m, 1H), 3.71-3.60 (m, 2H), 3.43 (s, 3H), 3.35-3.23
and 3.10-2.41 (m, 8H), 2.36-2.14 (m, 4H), 2.00-1.60 (m, 6H), 1.36 and 1.28 (d, J =
7.0Hz, 3H).
Example 1(4)
(11 α,15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-2,3-propano-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
[0067]

TLC: Rf 0.22 (ethyl acetate : methanol = 20 : 1);
NMR(CDCl
3): δ 7.38-7.10 (m, 4H), 5.75 (dd, J = 15.3, 6.0Hz, 1H), 5.53 (dd, J = 15.3, 8.0Hz,
1H), 4.48-4.38 (m, 3H), 4.00-3.89 (m, 1H), 3.63-3.53 (m, 1H), 3.46-3.17 (m, 5H), 2.95-2.14
(m, 11 H), 1.99-1.62 (m, 3H),1.06-0.84 (m, 2H), 0.58-0.44 (m, 2H).
Formulation example 1
[0068] The following compounds were admixed in conventional method and punched out to obtain
100 tablets each containing 0.5 mg of active ingredient.
· (11α,15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxy-methylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol
· α-cyclodextrin
----- 250 mg (active ingredient 50 mg)
· Carboxymethylcellulose calcium ------ 200 mg
· Magnesium stearate ----- 100 mg
· Micro crystalline cellulose ----- 9.2 g
Formulation example 2
[0069] The following components were admixed in a conventional method, and the solution
was sterilized in a conventional method, placed 1 ml portions into ampoules and freeze-dried
in a conventional method to obtain 100 ampoules each containing 0.2 mg of active ingredient.
· (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxy-methylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-alcohol
· α-cyclodextrin
----- 100 mg (active ingredient 20 mg)
· Mannit ------ 5 g
· Distlled water ----- 100 ml
1. A 5-thia- ω-substituted phenyl-prostaglandin E alcohol of the formula (I)

(wherein, --A-- is absent or --A-- is methylene or ethylene,
R1 is hydrogen, C1-6 alkyl, phyenyl-C1-6 alkyl, C2-6 alkanoyl, or phyenyl-C2-6 alkanoyl,
R2 is oxo or halogen,
R3 is hydrogen or hydroxy,
R4a and R4b are, independently, hydrogen or C1-4 alkyl,
R5 is phenyl substituted with the following group:
i) 1-3 of group selected from the group consisting of
C1-4 alkyloxy-C1-4 alkyl,
C2-4 alkenyloxy-C1-4 alkyl,
C2-4 alkynyloxy-C1-4 alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,
phenyloxy-C1-4 alkyl,
phyenyl-C1-4 alkyloxy-C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl,
C2-4 alkenylthio-C1-4 alkyl,
C2-4 alkynylthio-C1-4 alkyl,
C3-7 cycloalkylthio-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl,
phenylthio-C1-4 alkyl, and
phyenyl-C1-4 alkylthio-C1-4 alkyl,
ii)
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4 alkyloxy-C1-4 alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or
C1-4 alkylthio-C1-4 alkyl and halogen,
iii) haloalkyl or hydroxy-C1-4 alkyl, or
iv) C1-4 alkyl and hydroxy;
--- is a single bond or a double bond)
or cyclodextrin clathrate thereof.
2. The compound according to claim 1, wherein R2 is oxo.
3. The compound according to claim 1, wherein R2 is halogen.
4. The compound according to claim 1, wherein R3 is hydrogen.
5. The compound according to claim 1, wherein R3 is hydroxy.
6. The compound according to claim 1, wherein R
5 is phenyl substituted with i) 1-3 of substituent(s) selected from
C1-4 alkyloxy-C1-4 alkyl,
C2-4 alkenyloxy-C1-4 alkyl,
C2-4 alkynyloxy-C1-4 alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,
phenyloxy-C1-4 alkyl,
phyenyl-C1-4 alkyloxy-C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl,
C2-4 alkenylthio-C1-4 alkyl,
C2-4 alkynylthio-C1-4 alkyl,
C3-7 cycloalkylthio-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkylthio-)-C1-4 alkyl,
phenylthio-C1-4 alkyl, or
phyenyl-C1-4 alkylthio-C1-4 alkyl.
7. The compound according to claim 1, wherein R
5 is phenyl substituted with ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4 alkyloxy-C1-4 alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy, or
C1-4 alkylthio-C1-4 alkyl and halogen
8. The compound according to claim 1, wherein R5 is phenyl substituted with iii) haloalkyl, or hydroxy-C1-4 alkyl.
9. The compound according to claim 1, wherein R5 is phenyl substituted with iv) C1-4 alkyl and hydroxy.
10. The compound according to claim 1, which is (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,
(11 α,15α,13E)-9-oxo-11,15-dihydroxy-1 6-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-1
3-en-1-alcohol,
(11 α,15α,13E)-9-oxo-11,15-dihydroxy-16-methyl-16- (3-methyl-4-hydroxyphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,
(11α,15α,13E) -9-oxo-11,15-dihydroxy-16-methyl-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol,
or
(11 α,15 α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-2,3-propano-17,18,19,20-tetranor-5-thiaprost-13-en-1-alcohol.
11. A process which comprises reacting a compound of the formula (II)

(wherein,
R1-1 is C1-6 alkyl, phenyl-C1-6 alkyl, C2-6 alkanoyl, phenyl-C2-6 alkanoyl, or a protecting
group of hydroxy which is removed under an acidic condition,
R3-1 is hydrogen, or hydroxy protected by a protecting group of hydroxy which is removed
under an acidic condition,
R10 is a protecting group of hydroxy which is removed under an acidic condition,
R5-1 is the same meaning of R5 in claim 1 provided that a hydroxy in the group represented by R5-1 is protected by a protecting group of hydroxy which is removed under an acidic condition,
and
the other symbols are the same meaning as defined hereinbefore)
for removal of a protecting group under an acidic condition to obtain a compound of
the formula (I)

(wherein, all the symbols are the same meaning as defined in claim 1).
12. A pharmaceutical composition comprising a 5-thia- ω-substituted phenyl-prostaglandin
E alcohol of the formula (I), or cyclodextrin clathrate thereof as an active ingredient.